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1.
J Biol Chem ; 294(51): 19740-19751, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31712311

RESUMO

In cancer, aberrant growth factor receptor signaling reprograms cellular metabolism and global gene transcription to drive aggressive growth, but the underlying mechanisms are not well-understood. Here we show that in the highly lethal brain tumor glioblastoma (GBM), mTOR complex 2 (mTORC2), a critical core component of the growth factor signaling system, couples acetyl-CoA production with nuclear translocation of histone-modifying enzymes including pyruvate dehydrogenase and class IIa histone deacetylases to globally alter histone acetylation. Integrated analyses in orthotopic mouse models and in clinical GBM samples reveal that mTORC2 controls iron metabolisms via histone H3 acetylation of the iron-related gene promoter, promoting tumor cell survival. These results nominate mTORC2 as a critical epigenetic regulator of iron metabolism in cancer.


Assuntos
Neoplasias Encefálicas/metabolismo , Epigênese Genética , Glioblastoma/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ferro/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Histonas/química , Humanos , Proteínas Imediatamente Precoces/metabolismo , Metaboloma , Camundongos , Transplante de Neoplasias , Regiões Promotoras Genéticas , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piruvato Desidrogenase (Lipoamida)/metabolismo , Transdução de Sinais
2.
Org Biomol Chem ; 17(41): 9129-9134, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31584055

RESUMO

A synthesis method of doubly linked flavan dimers is reported via the acid-promoted annulation reaction using nascent catechins, (+)-catechin or (-)-epicatechin, as a dianionic partner and an ethylenedioxy-bridged flavan as a dicationic partner. Procyanidins A1 and A2 were synthesized. On the high regioselectivity of the annulation reactions, model experiments and computational studies were carried out.

3.
Int J Mol Sci ; 19(10)2018 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-30347859

RESUMO

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells.


Assuntos
Carcinogênese/metabolismo , Glucose/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Transdução de Sinais , Animais , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/genética
4.
Acta Neuropathol Commun ; 12(1): 40, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38481314

RESUMO

DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global "hypomethylator phenotype", are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Camundongos , Animais , Glioblastoma/patologia , Linhagem Celular Tumoral , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Metilação de DNA , Fenótipo , Neoplasias Encefálicas/patologia , DNA/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas Tirosina Quinases/genética
5.
Metabolites ; 11(4)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916219

RESUMO

Metabolic reprogramming is an emerging hallmark of cancer and is driven by abnormalities of oncogenes and tumor suppressors. Accelerated metabolism causes cancer cell aggression through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. However, the mechanisms by which a shift in the metabolic landscape reshapes the intracellular signaling to promote the survival of cancer cells remain to be clarified. Recent high-resolution mass spectrometry-based proteomic analyses have spotlighted that, unexpectedly, lysine residues of numerous cytosolic as well as nuclear proteins are acetylated and that this modification modulates protein activity, sublocalization and stability, with profound impact on cellular function. More importantly, cancer cells exploit acetylation as a post-translational protein for microenvironmental adaptation, nominating it as a means for dynamic modulation of the phenotypes of cancer cells at the interface between genetics and environments. The objectives of this review were to describe the functional implications of protein lysine acetylation in cancer biology by examining recent evidence that implicates oncogenic signaling as a strong driver of protein acetylation, which might be exploitable for novel therapeutic strategies against cancer.

6.
Nat Commun ; 12(1): 5341, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504070

RESUMO

Polycomb repressive complexes-1 and -2 (PRC1 and 2) silence developmental genes in a spatiotemporal manner during embryogenesis. How Polycomb group (PcG) proteins orchestrate down-regulation of target genes upon differentiation, however, remains elusive. Here, by differentiating embryonic stem cells into embryoid bodies, we reveal a crucial role for the PCGF1-containing variant PRC1 complex (PCGF1-PRC1) to mediate differentiation-associated down-regulation of a group of genes. Upon differentiation cues, transcription is down-regulated at these genes, in association with PCGF1-PRC1-mediated deposition of histone H2AK119 mono-ubiquitination (H2AK119ub1) and PRC2 recruitment. In the absence of PCGF1-PRC1, both H2AK119ub1 deposition and PRC2 recruitment are disrupted, leading to aberrant expression of target genes. PCGF1-PRC1 is, therefore, required for initiation and consolidation of PcG-mediated gene repression during differentiation.


Assuntos
Corpos Embrioides/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Histonas/genética , Células-Tronco Embrionárias Murinas/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 2/genética , Animais , Diferenciação Celular , Embrião de Mamíferos , Corpos Embrioides/citologia , Histonas/metabolismo , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Transgênicos , Células-Tronco Embrionárias Murinas/citologia , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Cultura Primária de Células , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Ubiquitinação
7.
Cancer Lett ; 478: 1-7, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32145344

RESUMO

Metabolic reprogramming is a central hallmark of cancer and is driven by abnormalites of oncogenes and tumor suppressors. This enables tumor cells to obtain the macromolecular precursors and energy needed for rapid tumor growth. Accelerated metabolism also translates into cancer cell aggression through epigenetic changes. The aberrant signaling cascades activated by oncogenes coordinate metabolic reprogramming with epigenetic shifts and subsequent global transcriptional changes through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. As the landscape of cancer cell metabolism has been elucidated, it is now time for this knowledge to be translated into benefit for patients. Here we review the recently identified central regulatory role for mechanistic/mammalian target of rapamycin complex 2 (mTORC2), a downstream effector of many cancer-causing mutations, in reprogramming the metabolic and epigenetic landscape. This leads to tumor cell survival and cancer drug resistance.


Assuntos
Redes Reguladoras de Genes , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Neoplasias/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Mutação , Neoplasias/genética
8.
Acta Histochem Cytochem ; 53(1): 1-10, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32201436

RESUMO

Cancer is widely considered to be a set of genetic diseases that are currently classified by tissue and cell type of origin and, increasingly, by its molecular characteristics. This latter aspect is based primarily upon oncogene gains, tumor suppressor losses, and associated transcriptional profiles. However, cancers are also characterized by profound alterations in cellular metabolism and epigenetic landscape. It is particularly noteworthy that cancer-causing genomic defects not only activate cell cycle progression, but regulate the opportunistic uptake and utilization of nutrients, effectively enabling tumors to maximize growth and drug resistance in changing tissue and systemic microenvironments. Shifts in chromatin architecture are central to this dynamic behavior. Further, changes in nutrient uptake and utilization directly affect chromatin structure. In this review, we describe a set of recent discoveries of metabolic and epigenetic reprogramming in cancer, and especially focus on the genomically well-characterized brain tumor, glioblastoma. Further, we discuss a new mode of metabolic regulation driven by epigenetic mechanisms, that enables cancer cells to autonomously activate iron metabolism for their survival. Together, these underscore the integration of genetic mutations with metabolic reprogramming and epigenetic shifts in cancer, suggesting a new means to identifying patient subsets suitable for specific precision therapeutics.

9.
Mol Cancer Res ; 18(8): 1142-1152, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32366675

RESUMO

Epigenetic regulation known for DNA methylation and histone modification is critical for securing proper gene expression and chromosomal function, and its aberration induces various pathologic conditions including cancer. Trimethylation of histone H3 on lysine 27 (H3K27me3) is known to suppress various genes related to cancer cell survival and the level of H3K27me3 may have an influence on tumor progression and malignancy. However, it remains unclear how histone methylation is regulated in response to genetic mutation and microenvironmental cues to facilitate the cancer cell survival. Here, we report a novel mechanism of the specific regulation of H3K27me3 by cooperatively two mTOR complexes, mTORC1 and mTORC2 in human glioblastoma (GBM). Integrated analyses revealed that mTORC1 upregulates the protein expression of enhancer of zeste homolog 2, a main component of polycomb repressive complex 2 which is known as H3K27-specific methyltransferase. The other mTOR complex, mTORC2, regulates production of S-adenosylmethionine, an essential substrate for histone methylation. This cooperative regulation causes H3K27 hypermethylation which subsequently promotes tumor cell survival both in vitro and in vivo xenografted mouse tumor model. These results indicate that activated mTORC1 and mTORC2 complexes cooperatively contribute to tumor progression through specific epigenetic regulation, nominating them as an exploitable therapeutic target against cancer. IMPLICATIONS: A dynamic regulation of histone methylation by mTOR complexes promotes tumor growth in human GBM, but at the same time could be exploitable as a novel therapeutic target against this deadly tumor.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Glioblastoma/patologia , Histonas/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , S-Adenosilmetionina/metabolismo , Regulação para Cima , Animais , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Transplante de Neoplasias
10.
Org Lett ; 16(16): 4106-9, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25072267

RESUMO

Stereoselective acylation of the E,E-vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved by using acid anhydrides and SnCl4. Acid anhydrides having alkyl chains gave the adducts in excellent stereoselectivity. The formal synthesis of khafrefungin has been accomplished by the methodology.


Assuntos
Acetais/química , Glicolipídeos/síntese química , Silanos/química , Acilação , Anidridos/química , Catálise , Glicolipídeos/química , Estrutura Molecular
11.
Org Lett ; 15(12): 3170-3, 2013 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-24490779

RESUMO

A concise and straightforward synthesis of 2,4,6-trimethyloctanoates was established by using the sequence of the vinylogous Mukaiyama aldol reaction and regio- and stereoselective reduction reactions. All isomers were obtained selectively in a few steps. The short step synthesis of septoriamycin A, an antimalarial and antileishmanial agent, has been achieved by this methodology.


Assuntos
Caprilatos/síntese química , Propionatos/síntese química , Caprilatos/química , Estrutura Molecular , Propionatos/química , Estereoisomerismo
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